Design of specific inhibitors of protein-protein interactions that are capable of turning off specific signaling pathways have an important bearing on the future of therapeutics. Cancer genome project has demonstrated that in many, if not all, tumors accumulate multiple mutations resulting in several dysregulated pathways favoring uncontrolled proliferation (Greenman et al., 2007; Weir et al., 2007). These combinations of dysregulated pathways may be necessary to overcome the multiple tumor suppressor functions present in differentiated cells (Bartkova et al., 2006; Jirina Bartkova, 2005; Weir et al., 2007). Specific targeting of multiple dysregulated pathways, either through a single agent or through multiple agents may provide useful advantage. Thus, drug targets that regulate multiple pathways are important. However, selectivity of inhibited pathways may be crucial to avoid off-target toxic effects. A classic example in oncology is that of imatinib, which inhibits Bcr-Abl kinase with significant degree of specificity (Druker, 2008).
Although small molecules are sometimes known to be protein-protein interaction inhibitors, they rarely exhibit low off-target effects. Secondary structure mimetics have been proposed as effective protein-protein interaction inhibitors (Banerjee et al., 2002; Saraogi and Hamilton, 2008; Walensky et al., 2004). Due to resemblance of the secondary structure mimetics to extant proteins, they may be superior to small molecules in causing lesser undesirable off-target effects. In many situations, a low nanomolar dissociation constant of receptor-drug complex is desirable or even mandatory (Overington et al., 2006). Many protein-protein interactions are weak and attaining high enough affinity for a secondary structure mimetic where the parent protein-protein interaction is weak remains a major challenge. Since many proteins are oligomeric in nature, we propose that properly designed oligomeric secondary structure mimetics (more than one secondary structure mimetic connected by a designed tether) may be a simple way to enhance affinity in such cases.
S100 family of proteins has been implicated in wide variety of tumors, although their precise role is still unclear. Increased levels of S100B are observed in several tumors (Harpio and Einarsson, 2004) and it has been suggested to contribute to tumor progression by interacting and down-regulating p53 and inhibiting its function as a tumor suppressor (Lin et al., 2001; Rustandi et al., 1999; Rustandi et al., 2000; Rustandi et al., 1998b; Wilder et al., 1998). Recent work suggests that other pro-survival pathways may also be regulated by S100B (Brozzi et al., 2009). Thus, inhibition of S100B may simultaneously regulate several key growth regulatory pathways and exert broad anti-tumor effect. Classes of melanomas and gliomas are prime examples of cancers where over-expression of S100B plays a crucial role in cancer development and progression (Markowitz et al., 2005). Thus, there is a real need of agents that block S100B interaction with other proteins.
Keeping in purview the hitherto reported prior art, it may be summarized that most of the therapeutic efforts have been focused on small molecules. There is a recent surge of interest in peptides, although the market is still small. Recent scientific developments have created tremendous opportunity in the therapeutic field. A number of peptides are now in market, but mostly in different phases of trial. However, none are known against melanoma and certainly not with high efficacy. Consequently, there is a dire need to design specific inhibitors of protein-protein interactions that are capable of turning off specific signaling pathways which have an important bearing on the future of therapeutics.